The objective of the proposed research is to identify the genetic and biological bases for features of the Down Syndrome phenotype. This will be accomplished through the transfer of genes and chromosomal segments (cloned as YACs, BACs, and/or PACs) from human chromosome 21 through transgenic procedures into the mouse germline, producing dosage imbalance for the transferred sequences. Attempts will be made to generate mice carrying chromosome 21 through physical transfer of the chromosome into mouse embryonic stem cells. The transgenic animals will be analyzed for neurobiological and other features of the of the DS phenotype. Analysis will also be performed on tissues from transgenic animals to determine those genes whose expression changes in response to the presence of extra copies of genes or chromosomal segments.